The incidence of cutaneous melanoma (CM) has dramatically increased over the past several decades. Like other cancers, melanomas most likely result from an interaction between environmental carcinogens, such as ultraviolet radiation, and genetics. Evidence so far suggests that mutations in growth regulatory genes, such as RAS and INK4alpha, contribute to the development of CM. Less understood, however, is the role of DNA repair in melanoma tumorigenesis. Defects in nucleotide excision repair (NER), as seen in the clinical disorder xeroderma pigmentosum, lead to a greatly exaggerated risk of developing CM. The mechanism, however, underlying this clinical observation is largely uncharacterized. The long-term objective of this project is to understand the role of nucleotide excision repair in the pathogenesis of cutaneous melanoma. Specifically, the proposed studies will evaluate if (1) ongoing NER is critical in restricting spontaneous melanoma tumor growth; (2) novel targets for mutation in addition to RAS and INK4alpha emerge in the absence of NER; (3) loss of INK4alpha disrupts the UV response in NER-deficient cells. To test these hypotheses, the Candidate will use murine models to (I) examine, in vivo, the biological consequence of NER loss on the formation of melanomas and (II) characterize, in vitro the impact of INK4alpha loss on the UV-response in NER-deficient murine embryonic fibroblasts (MEFs). A more thorough understanding of the DNA repair mechanisms could lead to better strategies for prevention and therapy. Dr. Tsao received both his M.D. and Ph.D. from Columbia University. After completing a residency in Dermatology, he returned to the laboratory in order to focus on human melanoma genetics. With the proposed studies, he is taking a dramatic departure from previous studies and immersing himself in mice cancer genetics. Dr. Tsao is an Assistant Professor of Dermatology at Harvard Medical School and an associate physician at the Massachusetts General Hospital Melanoma Center. Dr. Tsao is committed to the study of cutaneous melanoma and the career development activities outlined in this application will allow him to become fully independent.